This work is licensed under a Creative Commons Attribution 4.0 International License.
Scand J Work Environ Health 2021;47(8):565-581 Published online: 15 Sep 2021, Issue date: 01 Nov 2021 doi:10.5271/sjweh.3982
Associations of working conditions and chronic low-grade inflammation among employees: a systematic review and meta-analysis
by Kaltenegger HC, Becker L, Rohleder N, Nowak D, Weigl M
This is the first systematic review and meta-analysis on associations of working conditions and chronic low-grade inflammation solely based on prospective studies. It finds that workplace physical activity interventions were effective in reducing employees’ inflammation.
However, the current research base is limited and heterogeneous, highlighting the need for prospective studies to advance knowledge regarding pathways from work stress to ill-health.
Affiliation: Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Z i e m s s e n s t r a ß e 1 , 8 0 3 3 6 , M ü n c h e n , G e r m a n y . helena.kaltenegger@med.uni-muenchen.de
Refers to the following texts of the Journal: 2010;36(2):96-108 2014;40(1):5-18 2015;41(5):491-503 2020;46(1):19-31 2021;47(3):200-207
Key terms: chronic low-grade inflammation; employee; health;
immune system; inflammation; inflammation; inflammatory biomarker;
information and communication technology; job; meta-analysis;
occupational stress; systematic review; work; working condition This article in PubMed: www.ncbi.nlm.nih.gov/pubmed/34523689
Additional material
Please note that there is additional material available belonging to this article on the Scandinavian Journal of Work, Environment & Health -website.
R eview
Scand J Work Environ Health. 2021;47(8):565–581. doi:10.5271/sjweh.3982
Associations of working conditions and chronic low-grade inflammation among employees: a systematic review and meta-analysis
by Helena C Kaltenegger, MSc,1 Linda Becker, PhD,2 Nicolas Rohleder, PhD,2 Dennis Nowak, MD,1 Matthias Weigl, PhD 1, 3
Kaltenegger, HC, Becker L, Rohleder N, Nowak D, Weigl M. Associations of working conditions and chronic low-grade inflammation among employees: a systematic review and meta-analysis. Scand J Work Envion Health. 2021;47(8):565–581.
doi:10.5271/sjweh.3982
Objectives Chronic low-grade inflammation has been identified as a key pathway linking stress experience to human health. However, systematic evaluations on the relationship of work stress and immune function are scarce and predominantly based on cross-sectional studies. We performed a systematic review and meta-analysis of prospective studies on associations of working conditions and inflammatory biomarkers.
Methods In line with our previously established study protocol and the PRISMA-guidelines, we systematically searched electronic databases for prospective studies on working conditions as well as workplace interven- tions and inflammatory markers in employees. We classified studies (by design, type of exposure/intervention, outcome) and performed rigorous risk-of-bias assessments. Studies were summarized qualitatively, and a meta- analysis was conducted.
Results We identified 23 eligible studies (N=16 432) with a broad scope of working conditions and inflammatory markers. For interventional designs, we differentiated between individual-directed/behavioral (including physical and mental) and organization-directed/structural interventions. Workplace physical exercise interventions were associated with a decrease in C-reactive protein (k=5; d=-0.61; P<0.001). For other workplace interventions, ie, mental and organizational/structural, results were inconclusive. Concerning observational studies, dimensions of the job demand–control(–support) model were most frequently investigated, and results showed weak – if any – associations with inflammatory markers.
Conclusions The research base was heterogeneous and high-level evidence was limited. More prospective stud- ies are needed with broader consideration of work stressors and inflammatory markers. For practical occupational health management, exercise interventions are effective measures to reduce chronic low-grade inflammation.
Key terms health; immune system; inflammatory biomarker; information and communication technology; job;
occupational stress; work.
1 Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Munich, Germany.
2 Chair of Health Psychology, Institute of Psychology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
3 Institute for Patient Safety, University Hospital Bonn, Bonn, Germany.
Correspondence to: Helena C. Kaltenegger, MSc, Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Ziemssenstraße 1, 80336, München, Germany. [E-mail: helena.kaltenegger@med.uni-muenchen.de]
Given the profound transformation of work in the age of digitalization, investigations into ramifications for employee health are of crucial importance. There is substantial evidence for associations between exposure to workplace-related stressors and risk of physical as well as mental morbidity, including cardiovascular dis- eases (CVD), metabolic conditions, depression, etc, and mortality (1–9). Over the past years, research on work
stress has expanded the focus on job task characteristics [such as described in Karasek’s job strain model (10)]
to organizational factors (such as working hours or organizational justice) and also broader labor market conditions (such as job insecurity) and their effects on employee health (11–14). Work stress is typically clas- sified as chronic stress, ie, prolonged or repeated stress exposure, although there is no clear time point to dif-
This work is licensed under a Creative Commons Attribution 4.0 International License.
ferentiate between chronic and acute stressors (15–17).
In general, the human stress response involves – besides the engagement of the main stress systems [ie, autonomic nervous system (ANS) and hypotha- lamic-pituitary-adrenocortical (HPA) axis] – complex effects on the immune system most importantly with up- regulation of inflammatory pathways and down- regulation of cellular immunity (18–21). While in the short term these adaptations serve protective functions (22, 23), sustained and systemic low-grade inflamma- tion implies a dysregulation of the immune system and has been suggested as a mediator in the pathogenesis of chronic diseases (20, 24–27). Particularly, inflam- matory biomarkers, such as C-reactive protein (CRP), interleukin-6 (IL-6), but also leukocytes, are involved in the atherosclerotic process (28, 29).
Reviews and meta-analyses in the field of psycho- neuroimmunology demonstrate a large body of evidence that psychosocial distress affects immunological and inflammatory activity (17, 30–32). Specifically for work stress, studies reported associations between adverse working conditions and chronic low-grade inflammation in employees, as for instance effort–reward imbalance (ERI) (33), long working hours (34), job strain and poor social support (35, 36). However, two pivotal limitations arise from the current literature base.
First, conclusive and systematic syntheses of the cur- rent knowledge base as well as quantitative aggregation of effects of work-related stress on employees’ chronic low-grade inflammation are scarce. Previous reviews and meta-analyses have focused on associations of psychosocial job stress (37, 38) and herein particularly ERI (39) with immune and inflammatory markers. Those reviews have the limitation of including a significant number of cross-sectional studies, what limits inferences concerning cause-effect relationships.
Secondly, collated evidence is lacking with regard to effects of other work exposures – besides the commonly studied psychosocial work factors – on employees’
immune function. With the ubiquitous and ever-increas- ing use of information and communication technologies (ICT) in the workplace, associated risks of profession- als’ stress experience have become a phenomenon of growing scholarly interest. Human interaction with ICT at work is suggested as a potential source of negative psychological and biological sequelae for health and well-being (40, 41). Yet, as far as we are aware, knowl- edge gaps exist with respect to how working conditions related to the omnipresence and use of ICT and con- comitant new demands, but also resources for employees (42) have effects on physiological stress responses in terms of low-grade inflammation.
A review based on prospective studies allows for conclusions on a higher level of evidence and for infer- ences concerning temporal order and direction of effects
in the interplay of workplace stressors and inflammatory reactivity as a risk factor to serious long-term diseases (43). Beyond temporal sequence, ie, the exposure pre- cedes the outcome, one important indicator of causation is reversibility, ie, mitigation of work stress reduces the health risk (13, 44). The consideration of interventional studies with high-quality designs [ie, randomized trials (45)] in addition to observational prospective stud- ies, may therefore not only provide a more complete summary of the evidence, but also deeper insights into potential cause-effect relationships between work stress- ors and inflammatory markers.
We conducted a systematic review and meta-analysis to determine the present evidence base on prospective associations between various working conditions and chronic low-grade inflammation in employees. More specifically, we aimed to (i) systematically summarize the current research base and establish quantitative estima- tions of associations. Furthermore, we sought to (ii) detect studies on ICT use at work and inflammatory markers.
Lastly, we aimed to (iii) identify and evaluate workplace- related interventions to decrease inflammation.
Methods
Protocol and registration
First, a systematic review protocol was developed and published (46). The review was registered in the PROS- PERO-database (registration ID: CRD42020166887). It adheres to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (47;
PRISMA-checklist upon request). No major deviances from the original protocol were undertaken. Minor adap- tations related to the use of software, waiver of graphical synthesis, and use of AMSTAR-2 instead of GRADE (for details, please see below).
Eligibility criteria
We searched for studies on associations between work- ing conditions and inflammation fulfilling the follow- ing PECOS/PICOS-criteria: Participants (P): adult employees/workers/professionals. Clinical samples with particular diagnoses as well as specific profes- sional groups, like military personnel, athletes, artists, and students were excluded. Exposures/interventions (E/I): all kinds of working conditions and workplace- related interventions, including psychosocial, mental, and physical. There were no a-priori restrictions by type of workplace intervention, meaning all measures aiming at occupational health promotion or well-being on the job, conducted on or off site as well as during
Kaltenegger et al
or outside working hours, were considered. Studies on environmental hazards, ie, chemical or biological agents and extreme heat, as well as nutritional, pharmaceutical, or nutraceutical interventions were not eligible. Further- more, we excluded studies on shiftwork and exclusive shiftwork samples (48, for a review) as well as studies on socioeconomic status as exposure. A particular objec- tive of our review were effects of work-related use of digital technologies and media, defined as all electronic devices (hardware), applications (software), and means of communication, such as computers, mobile phones, messaging systems, autonomous systems, etc. Compara- tors (C): workers not or exposed to a lower extent to working conditions/workplace interventions of interest.
Outcomes: pre-defined biomarkers of inflammation within three main categories (cells, plasma molecules, intracellular processes) measured in blood or saliva (see supplementary material, www.sjweh.fi/article/3982, table S1). Study design (S): prospective studies with at least one follow-up measure, ie, at least two consecu- tive measurements of the inflammation outcome. We included observational (eg, cohort) and interventional studies, ie, randomized controlled trials (RCT) and non-randomized studies of interventions (NRSI, eg, before-after studies). Laboratory or simulation studies were not eligible. We included original research articles in the languages English or German published in peer- reviewed journals from 1982 until present. Conference proceedings, study protocols, and theses were excluded.
Information sources
As primary information source, we conducted a sys- tematic search in five electronic databases, includ- ing PubMed/MEDLINE, Embase, PsycINFO, Web of Science, and Cochrane’s CENTRAL. Our search was finalized in November 2020. In addition, we performed citation searching of included studies in Google Scholar (forward search) and hand-searching of reference lists of included studies and relevant reviews (backward search).
Search and study selection
We developed a four-tier search string comprising a broad spectrum of terms related to the specified PECOS/
PICOS elements (see also 46). The four blocks were linked with the Boolean operator “AND” and within the blocks the terms were combined by “OR”. The screen- ing procedure of retrieved records was conducted in Rayyan (49). Two reviewers independently performed systematic and stepwise assessment of eligibility (HK, MW). First, titles and abstracts were screened and then full-texts were assessed. The title and abstract screening were pre-tested, in order to ensure a joint understanding
of the eligibility criteria. Discrepancies and uncertain- ties were resolved by discussion as well as consultation of other review members until consensus was reached.
Data collection process and data items
Two reviewers (HK, MW) extracted data of included studies in a pilot-tested Excel sheet (table S2) that was based on the Cochrane Consumers and Communication Group’s template (50). In case of missing information, we contacted authors. We obtained additional data from four authors. For multiple publications of identi- cal data, only one study with longer follow-up period was included. Information was extracted on (46): study characteristics (authors, year, design, location, follow- up, occupational setting); P=participants’ professional characteristics, age, gender, ethnicity, health-related variables, sample size, recruitment method, relevant inclusion/exclusion criteria; E/I and C=type and descrip- tion of working condition/workplace intervention and comparators, theoretical foundation, and assessment;
O=type and assessment of outcomes; statistical analyses, results, and moderators/control of confounders. Where reported, we extracted data from adjusted models for baseline biomarker levels and/or important covariates such as age or sex. After data extraction, professional samples were grouped into occupational settings based on the ILO classification of industries and sectors (51).
Risk of bias in individual studies
Two reviewers (HK, MW) performed standardized risk of bias (RoB) assessments, and systematic evaluations were established after consensus. For RCT, the updated version of the commonly used Cochrane risk-of-bias tool (RoB 2; 52), and for NRSI, ROBINS-I was applied (53). Observational studies were assessed with the Qual- ity of Reporting of Observational Longitudinal Research checklist (54). A summary score was calculated with higher scores indicating better quality (54).
Synthesis of results
Synthesis of results comprised three steps: First, we clustered studies by design, exposure/intervention, and outcome. Concerning exposures/interventions, we applied our pre-defined classification system: stud- ies were categorized based on underlying theoretical models and specific exposure features: mental versus non-mental, acute versus chronic, investigation of digital technology use (for definitions, see above and 46). Sec- ond, we provided a qualitative summary of all included studies in narrative and tabular format. In addition, main results were visualized by means of arrows indicating direction of effects. Third, where possible, we performed
quantitative syntheses of sufficiently similar studies.
Otherwise, results were summarized narratively for at least two studies within one cluster. A random-effects meta-analysis was conducted utilizing Meta-Essentials (55). Heterogeneity was evaluated using Q statistic with p-value and I2 statistic. In case of low heterogeneity, additionally a fixed-effects model was applied. As the majority of studies were based on controlled designs with repeated measurements, we chose an effect size that accounts for pre-post changes in different groups.
In particular, we calculated the recommended pretest- posttest-control group effect size dppc2, according to the following formula (56, 57):
(T=treatment group; C=control group)
For the interpretation, the operational definition by Cohen (58) of d-values of 0.2, 0.5, and 0.8 represent- ing small, medium, and large effect sizes was used. As a sensitivity analysis, we excluded studies attributed a high RoB.
Risk of bias across studies
In order to assess RoB across studies, we used funnel plots, tests for funnel plot asymmetry (59), and the Trim- and-Fill procedure (60, 61). Furthermore, we applied the appraisal instrument AMSTAR-2 for evaluation of the quality of our review (62).
Results
Study selection
The database search yielded a total of N=28 623 records.
After removal of duplicates, 24 062 records remained and were screened by title and abstract; 23 956 records were discarded. Besides, we identified 2285 additional records and 3 reviews relevant to our research question, which were screened for further eligible studies (38, 63, 64). In total, 106 full-texts were assessed in detail, of which 83 studies did not meet our inclusion criteria
(list of excluded studies upon request). Eventually, 23 studies were included in the qualitative and 5 studies in an additional quantitative analysis. A PRISMA flow diagram depicts the study selection process (figure 1).
Study characteristics
The characteristics of all included studies are presented in table 1. There were two major clusters of study designs:
16 interventional studies, including 8 RCT (65–72) and 8 NRSI (73–80) as well as 7 observational studies (81–87).
The majority of studies (k=13) (65–68, 70, 73, 75–77, 79, 80, 84, 86) came from Europe, 4 from Asia (71, 72, 83, 87), and 2 from the USA (69, 78) (location in 4 studies not specified). In sum, data from N=16 432 (including dropouts, see table S2) participants were included in our review. Samples were based on differ- ent occupational settings, most frequently public service (k=7) (68, 70, 73, 78, 82, 84, 86), followed by health services (k=5) (65, 67, 69, 77, 85). The majority of stud- ies excluded employees with particular diseases, such as CVD, diabetes, inflammatory conditions, and/or use of specific medication (table S2, for more details). We found high heterogeneity in studied work-related expo- sures/interventions. According to our pre-defined scheme for model- and feature-based classification of working conditions (46), we retrieved 5 studies that were based on established job stress models, including job demands and resources like job control, decision latitude, and workplace social support (73, 82, 83, 86, 87). Other or modified job stress models were examined in 2 studies (84, 85). Concerning specific features, we categorized 15 studies as investigating psychosocial or mental working conditions/interventions (65, 66, 69, 72–74, 76, 78, 80, 82–87) and 8 studies as assessing physical work-related exposures/interventions (67, 68, 70, 71, 75, 77, 79, 81). Furthermore, 3 studies (72, 74, 81) examined pre- dominantly acute effects. Remarkably, we did not retrieve prospective studies on work-related ICT use, apart from one study reporting effects of a web-based workplace intervention (66). Concerning inflammatory outcomes, included studies covered all pre-defined categories (table S1). Most frequently surveyed were plasma molecules including CRP (67, 68, 70, 71, 73, 75, 77–80, 82–84, 86, 87) and cytokines (66, 67, 71, 73, 74, 79–82, 84–86).
Inflammation-related processes on cell level, ie, leukocyte counts, were investigated in 3 studies (72, 85, 87). Intra- cellular processes, including gene expression (65, 72) and transcription factors (69), were also assessed in 3 studies (see tables 1 and S2).
Risk of bias within studies
The results of the RoB assessments (per domain and overall) for RCT and NRSI as well as of the quality of 𝑑𝑑𝑝𝑝𝑝𝑝𝑝𝑝𝑝 =𝑐𝑐𝑃𝑃��𝑀𝑀𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝,𝑇𝑇− 𝑀𝑀𝑝𝑝𝑝𝑝𝑝𝑝,𝑇𝑇� − (𝑀𝑀𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝,𝑐𝑐− 𝑀𝑀𝑝𝑝𝑝𝑝𝑝𝑝,𝑐𝑐)
𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝 �
𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝=�(𝑛𝑛𝑇𝑇− 1)𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝,𝑇𝑇2𝑛𝑛 + (𝑛𝑛𝐶𝐶− 1)𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝,𝐶𝐶2
𝑇𝑇+ 𝑛𝑛𝐶𝐶− 𝑝
𝑐𝑐𝑝𝑝= 1−4(𝑛𝑛 3
𝑇𝑇+ 𝑛𝑛𝐶𝐶− 𝑝)−1
Kaltenegger et al
reporting assessment for observational studies are shown in table S3. All RCT were appraised to have “some concerns” regarding their overall RoB. Evaluations for NRSI are presented separately for controlled and uncon- trolled studies and ranged from “serious” to “critical”
overall RoB. For observational studies, on average 20 of the 33 checklist criteria were reported, leading to a mean summary score of 0.62 (range 0.41–0.70).
Results of individual studies
In the following, results are described first for inter- ventional and second for observational studies. For interventional designs, we further distinguished between individual/behavioral (ie, physical and mental) and orga- nizational/structural interventions.
Interventional studies
Individual/Behavioral Interventions
Physical Interventions. We found seven studies assess- ing effects of workplace physical activity/exercise inter- ventions on inflammatory biomarkers, including five controlled (four RCT) and two uncontrolled studies.
With regard to RCT, two studies examined effects of worksite aerobic exercise interventions in laboratory (67) and cleaning personnel (68). Murphy et al (70) investigated the influence of a walking program in
civil servants. Respective control groups (CG) received either no training (67, 70) or lectures (68). In a further RCT, effects of a workplace-based yoga intervention were assessed in industry employees against a wait-list CG (71). A controlled study (ie, comparison to passive CG) investigated a cycling to work intervention in professionals of a health insurance company (75). Two uncontrolled NRSI were identified: a leisure time physi- cal activity program in a road maintenance company initiated by the employer (79) and a promotional cam- paign for stair use in a hospital (77). All studies explored plasma molecules, most frequently CRP. Results per marker are presented in table 2.
A meta-analysis was performed for CRP based on the five controlled studies (see figure 2). Results showed a combined effect size of Cohen’s d=-0.61 (range -1.04– -0.18) that was significantly different from zero [z(242)=-3.47, P<0.001, 95% confidence interval (CI) -1.09– -0.12]. This effect was medium-to-large in size and indicated that the physical interventions resulted in a significant reduction of workers’ CRP levels. The studies included in this pooled effect size showed no sig- nificant heterogeneity (Q=5.64, P =0.228, I2=29.1%). An additional fixed-effects meta-analysis revealed similar results. Exclusion of one study appraised with “serious”
RoB (75) resulted in an attenuated, yet still significant negative effect (d=-0.48, 95% CI -1.04–0.08, P=0.003).
With regard to other inflammatory markers, three
Figure 1
PRISMA Flow Diagram according to Moher et al. (47)
Records identified through database searching: n=28 623 (Initial search: n=26 620; update: n=2003)
ScreeningIncluded Eligibility Identification
Additional records identified through other sources: n=2285
(Backward search: n=1278; forward search:
n=1004; other sources: n=3)
Records after duplicates removed n=24 062
Records screened
n=24 062 Records excluded
n=23 956
Full-text articles assessed for eligibility
n=106
Full-text articles excluded n=83 - No relevant sample (10) - No exposure/ intervention
of interest (23) - No outcome of interest
(15)
- No longitudinal study/
outcome only measured once (21)
- Identical study (5) - No numerical data (2) - Other (7) Studies included in
qualitative synthesis n=23
Studies included in quantitative synthesis
(meta-analysis) n=5
Figure 1. PRISMA flow chart according to Moher et al (47).
Table 1. Study characteristics (N=23). [CRP=C-reactive protein; hs-CRP=high-sensitivity C-reactive protein; IFN-γ=interferon-gamma; IL=interleukin;
JDC(S)=job demand–control(–support) model; MCP-1=monocyte chemoattractant protein-1 (MCP-1); NR=not reported; NRSI=non-randomized study of intervention; RCT=randomized controlled trial; TNF-α=tumor-necrosis-factor-alpha; W=women].
Study Location Design Occupational
setting Sample
size Sex (% W) Age,
mean (SD) Exposure/
Intervention Outcome:
category Outcome:
biomarker Carlsson
et al (73) Denmark NRSI Public service 359 73.8 49.4 (0.4) Workplace
reorganization Plasma
molecules CRP, fibrinogen, IL-6
Christian &
Nussbaum (81) NR Observational Mixed 24 20 32.4 (7.4);
26.4 (7.7) a Occupational
physical demands Plasma
molecules IL-6
Dich et al (82) NR Observational Public service 7007 c 30 49 (5.8) JDC Plasma
molecules CRP, IL-6 Dunne et
al (65) Ireland RCT Health services 42 NR NR Attention-based
training program Intracellular
processes Gene expression (TNF-α, IL-6) Eguchi et
al (83) Japan Observational Mechanical and electrical engineering
2020 26.4 35.9 (10.4);
39.6 (10.1) b Workplace social
support Plasma
molecules hs-CRP
Elovainio et al
(84) England Observational Public service 4408 27.3 43.9 Organizational
justice Plasma
molecules hs-CRP, IL-6 Filaire et
al (74) NR NRSI Education 9 22.2 42.5 (2.4);
39.2 (2.5) b Lecturing to
students Plasma
molecules IL-10, IL-2, IL-4, TNF-α Geus et
al (75) Belgium NRSI Financial ser-
vices/ professional services
80 NR 49 (7); 43 (5) a Cycling to work Plasma
molecules CRP
Hasson et
al (66) Sweden RCT Media; culture;
graphical 303 38.3 NR Web-based stress
management system
Plasma
molecules TNF-α Hewitt et
al (67) England RCT Health services 20 NR 42 (8); 41 (8) a Aerobic exercise
program Plasma
molecules CRP, TNFα, IL-6 Korshøj et al
(68) Denmark RCT Public service 116 75.9 45.3 (8.6) Aerobic exercise
intervention Plasma
molecules Fibrinogen, hs-CRP Lebares et al
(69) US RCT Health services 83 d 48.2 d 28.6 (2.7) /
28.7 (2.2); 27.4 (2.1) / 28.8 (2.4) a
Enhanced stress
resilience training Intracellular
processes AP-1, NF-kappa B
Lee et al (85) NR Observational Health services 41 100 29.9 Job stress Cells, plasma
molecules White blood cells, IL-1β, IFN-γ, TNF-α Magnusson
Hanson et al (86) England Observational Public service 4638 28 49.6 (6.0) JDCS Plasma
molecules hs-CRP, IL-6 Meyer et
al (77) Switzerland NRSI Health services 77 54.5 42.8 (9.0) Promotional cam-
paign of stair use Plasma
molecules hs-CRP
Murphy et
al (70) Northern
Ireland RCT Public service 37 64.9 41.5 (9.3) Walking
intervention Plasma
molecules hs-CRP
Netterstrøm &
Hansen (76) Denmark NRSI Public transport 40 35 44.5; 43.5 a Outsourcing Plasma
molecules Fibrinogen Ramey et
al (78) US NRSI Public service 38 23.7 41.0 (7.6) Resilience training Plasma
molecules CRP
Shete et
al (71) India RCT Mixed 48 0 41.5 (5.2) Yoga training Plasma
molecules IL-6, TNF-α, hs-CRP Shirom et
al (87) Israel Observational Mixed 1121 34.2 47 (~9) JDCS Plasma mol-
ecules, cells hs-CRP, fibrinogen, white blood cell count Skogstad et
al (79) Norway NRSI Construction 121 36 41.8 (12);
42.6 (12.5) b Leisure-time physical activity intervention
Plasma
molecules CRP, IL-6, TNF-α, MCP-1 Wachi et
al (72) Japan RCT Mixed 40 0 38.4 (8.4) Recreational
music-making Intracellular processes;
cells
IFN-γ mRNA, IL-2 mRNA, IL-6 mRNA, IL-10 mRNA, Leukocyte counts Wultsch et
al (80) Austria NRSI Mixed 34 11.8 36.4 (8.9); 42.3
(11.2) a extended working
periods Plasma
molecules CRP, IL-6
a Age reported separately per group (control, intervention).
b Age reported separately for men and women.
c Only 39% of the initial sample (with complete biomarker data) were relevant to this review.
d Pooled data of two trials.
Kaltenegger et al
studies examined pro-inflammatory cytokines and two found reductions in IL-6 (71, 79) and TNF-α (67, 71), respectively.
Mental Interventions. We identified five studies on mental interventions, including four RCT (65, 66, 69, 72) and one uncontrolled study (78). Two RCT scrutinized meditation- and/or mindfulness-based train- ings, one among emergency department professionals (65) and one in medical residents (69). Similarly, a resilience training was examined in an uncontrolled
study among law-enforcement officers (78). Hasson et al (66) evaluated a web-based health promotion tool in IT and media workers, which in the intervention group (IG) additionally included classical stress man- agement exercises (eg, time-management, relaxation) and a chat. A cross-over study assessed recreational music-making, ie, group drumming, in male corporate employees (72). All results are presented in table S4.
Concerning gene expression, findings were mixed with two significant intervention effects, ie, an upregulation
Table 2. Workplace physical interventions and inflammatory biomarkers. Order of studies per biomarker, by risk of bias assessment, and alphabet.
[CG=control group; CRP=C-reactive protein; IG=intervention group; IL-6=interleukin 6; TNF-α=tumor-necrosis-factor-alpha; ↓↓ Significant de- crease in inflammatory biomarker following intervention (and no significant change/ increase in control); ↓ Tendency for decrease in inflammatory biomarker, non-significant (and no change/ increase in control); — No significant differences in inflammatory biomarker (between groups/ within group); ↑ Tendency for increase in inflammatory biomarker, non-significant (and no change/ decrease in control); ↑↑ Significant increase in inflam- matory biomarker following intervention (and no change/ decrease in control)]
Marker and study Type of physical intervention (duration,
frequency) Follow-up:
period/number Key findings Direction of effect
CRP
Hewitt et al (67) a Aerobic exercise (brisk walking/light
jogging, 12 weeks, 4 times/week) 12 weeks/3 IG: significant reductions (week 1-4, 1-8), non- significant reduction (week 1-12)
CG: no significant changes
Between groups: no significant differences
↓↓ (week 1-4, 1-8)
↓ (week 1–12) Korshøj et al (68) a Aerobic exercise (indoor biking/running,
12 months, 2 times/week) 12 months/1 IG: no significant changes CG: significant increase
Between groups: significant difference
↓ Murphy et al (70) a Walking (8 weeks, 2 days/week) 8 weeks/1 IG: no significant changes
CG: no significant changes
Between groups: no significant difference
↓
Shete et al (71) a Yoga (3 months, 6 days/week) 3 months/1 IG: significant reduction CG: no significant change
Between groups: no significant difference
↓↓
Geus et al (75) b Cycling to work (1 year, at least
3 times/week) 12 months/2 IG: no significant changes
CG: no significant changes
Between groups: no significant differences
↓
Skogstad et al (79) c Leisure time physical activity (8 weeks) 15 months/2 Significant reduction (at 15 months) ↓↓
Meyer et al (77) c Stair use (12 weeks) 6 months/2 No significant changes following intervention — Fibrinogen
Korshøj et al (68) a Aerobic exercise (indoor biking/running,
12 months, 2 times/week) 12 months/1 IG: no significant change CG: significant increase
Between groups: no significant difference
— IL-6Hewitt et al (67) a Aerobic exercise (brisk walking/light
jogging, 12 weeks, 4 times/week) 12 weeks/3 IG: No significant changes CG: significant increase (week 1-4) Between groups: no significant differences
—
Shete et al (71) a Yoga (3 months, 6 days/week) 3 months/1 IG: significant reduction CG: no significant change
Between groups: significant difference
↓↓
Skogstad et al (79) c Leisure time physical activity (8 weeks) 15 months/2 Significant reduction (at 15 months) ↓↓
TNF-α
Hewitt et al (67) a Aerobic exercise (brisk walking/light
jogging, 12 weeks, 4 times/week) 12 weeks/3 IG: significant reduction (week 1-4), non- significant reductions (week 1-8, 1-12) CG: no significant changes
Between groups: no significant differences
↓
Shete et al (71) a Yoga (3 months, 6 days/week) 3 months/1 IG: significant reduction CG: no significant change
Between groups: significant difference
↓↓
Skogstad et al (79) c Leisure time physical activity (8 weeks) 15 months/2 No significant changes —
a Randomized controlled trial.
b Non-randomized study of intervention, controlled.
c Non-randomized study of intervention, uncontrolled.
of TNF-α mRNA (65) and a downregulation of IL-10 mRNA (72), and non-significant effects for other cyto- kine mRNA levels.
Organizational/Structural Interventions
We found four NRSI on organizational/structural inter- ventions. Two studies assessed effects of work reor- ganization. One investigated changes in physiological markers following a major reorganization of non-state public offices (73), and another measured physiological effects of outsourcing among bus drivers (76). Wultsch et al (80) examined inflammatory effects of extended daily working times in office workers and carpenters. In addition, we included one study among university pro- fessors that investigated acute inflammatory reactions in saliva after lecturing to students (74). All results are depicted in table S5. Due to “serious” and “critical” RoB appraisals, reported findings need to be interpreted with caution. The two studies that measured employees’ CRP found significant increases after the intervention (73), yet one just in younger participants (80). For fibrinogen, no studies showed significant changes (73, 76). Regard- ing cytokines, for IL-6 one (73) out of two studies (80) reported significant upregulations. For other cytokines, increases were observed in response to an acute work stressor, ie, lecturing (except for IL-10) (74).
Observational studies
Overall, seven observational studies were retrieved (table 3). Four studies (82, 83, 86, 87) applied Karasek’s job demand–control(–support) JDC(-S) model (10, 88): Job strain (82, 86, 87) and workplace social support (86, 87) were not prospectively related to CRP. Meanwhile, when the source of social support was specified, high supervisor support (in contrast to coworker support) was
associated with lower CRP among women but not men (83). Job demands were not related to fibrinogen and leukocyte count (87) as well as IL-6 (82, 86). However, there were indications for small protective effects of job control regarding fibrinogen (87) and IL-6 (86) among women and leukocyte counts among men (87). For social support, Shirom et al (87) found no effects, but notably Magnusson Hanson et al (86) showed that poor workplace support – albeit weakly – was linked to higher IL-6 levels, which partially mediated the association with diabetes.
Lee et al (85) investigated job stress in hospital nurses based on criteria related to the JDC(-S) model by compar- ing measures of objective (eg, data on staffing patterns) and subjective (ie, self-report data) stress: they identified significantly lower numbers of white blood cells in the group with high objective stress, but found no effects of subjective stress and for cytokines (85). Moreover, orga- nizational justice and inflammation were surveyed in a large cohort study (84): Among men, but not women, low self-reported justice was associated with increased CRP and IL-6 in the long-term. Besides these model-based studies, we found one small exploratory study that com- pared acute effects of occupational physical demands in two groups with high (eg, construction workers) and low (ie, sedentary work) risk of work-related musculoskeletal disorders (81): IL-6 levels were greater in the high-risk group yet showed opposed temporal patterns in the two groups (table 3).
Risk of bias across studies
Concerning the meta-analysis, the funnel plot indicated symmetry in the distribution of individual effect esti- mates suggesting absence of bias and heterogeneity (89).
As less than ten studies were included, tests for asym- metry were not used (90). Based on the Trim-and-Fill
De Geus et al (75) a
Hewitt et al (67) b
Korshøj et al (68)
Murphy et al (70)
Shete et al (71)
Combined effect size 0
1
2
3
4
5
6
-2,00 -1,50 -1,00 Cohen's d-0,50 0,00 0,50 1,00 Figure 2. Forrest plot of individual and combined
effect size(s) for workplace physical interventions and C-reactive protein. a Geus et al (75): results apply to the total study group (including men and women).
b Hewitt et al (67): only the last follow up measure (after 12 weeks) was considered for this meta analysis.
Kaltenegger et al
method, no studies were missing to the right of the mean, so the combined effect size did not have to be adjusted for publication bias (see figure S1). Our self-rating of the overall confidence in the results per AMSTAR-2 (62) was “high”, indicating that the review provides an accurate and comprehensive summary of available studies addressing our research question (AMSTAR-2 evaluation sheet available upon request).
Discussion
Sustained systemic low-grade inflammation has been identified as one of the major pathophysiological path- ways linking exposure to chronic stress and development of severe long-term diseases. A thorough and evidence- based understanding of the role of work stress exposure for inflammatory pathways is thus imperative to develop effective prevention and mitigation measures in occu- pational stress research. To the best of our knowledge, this is the first systematic review and meta-analysis on
Table 3. Work-Related Exposures and Inflammatory Biomarkers [CRP=C-reactive protein; IFN-γ=interferon-gamma; IL=interleukin; JDC(S)=job demand-control(-support) model; NS=not significantly/ no significant; TNF-α=tumor-necrosis-factor-alpha. ↑↑ Significant positive association between working condition and inflammatory biomarker; ↑ Tendency for positive association between working condition and inflammatory biomarker, non-significant; — No significant association between working condition and inflammatory biomarker; ↓ Tendency for negative asso- ciation between working condition and inflammatory biomarker, non-significant; ↓↓ Significant negative association between working condition and inflammatory biomarker; ↑↑* Significant increase in inflammatory biomarker (group comparison); ↑* Tendency for increase in inflammatory biomarker, non-significant (group comparison); —* No significant differences in inflammatory biomarkers (group comparison); ↓* Tendency for decrease in inflammatory biomarker, non-significant (group comparison); ↓↓* Significant decrease in inflammatory biomarker (group comparison).]
Marker and study Type of exposure Follow-up: period/
number Key findings Direction of effect
CRPDich et al (82) JDC ~10-11 years/2 Job demands, decision latitude, job strain NS correlated with CRP — Magnusson Hanson
et al (86) JDCS 10 years/2 Job demands, job control, job strain, workplace social support NS
associated with subsequent CRP —
Shirom et al (87) JDCS 18-22 months/1 Workload, perceived control, social support NS associated with CRP — Eguchi et al (83) Source-specific workplace
social support (supervisor, coworker)
1 year/1 Supervisor support significantly negatively related to CRP in women (β=-0.11, P<0.01), not significantly related to CRP in men Coworker support NS related to CRP
↓↓ (supervisor support, women) Elovainio et al (84) Organizational justice ~ 14 years/2 Organizational justice significantly negatively associated with CRP in
men (percentage change: -4.0, P=0.02); no associations in women ↓↓ (men)
— (women) Fibrinogen
Shirom et al (87) JDCS 18-22 months/1 Workload NS associated with fibrinogen
Control significantly negatively associated in females (β=-0.09, P<0.05), no associations in males
Social support NS associated with fibrinogen
Workload — Control ↓↓ (women)
Support — IFN-γ, IL-1β and TNF-α
Lee et al (85) Job stress (objective and subjective job stressors:
low vs. high)
8 months/8 IFN-γ: NS differences between low vs. high objective and subjective
job stress —*
IL-1β: NS differences between low vs. high objective and subjective
job stress —*
TNF-α: Marginally lower level of TNF-α (ng/ml) in high objective job stress group (Mdn=1.7) compared to low (Mdn=2.2, P=0.07) NS differences between low vs. high subjective job stress
↓*
IL-6Dich et al (82) JDC ~10-11 years/2 Job strain, job demands, decision latitude NS correlated with IL-6 — Magnusson Hanson
et al (86) JDCS 10 years/2 Social support a associated with subsequent IL-6 (β=0.03, P=0.051) Job demands and control a NS associated with subsequent IL-6 Sex stratified analyses: Job control a significantly associated to sub- sequent IL-6 in women (β=0.07, P<0.05), not men
Support a ↑ Demands — Control — Control a ↑↑ (women) Christian &
Nussbaum (81) Occupational physical
demands (high vs low) 1 working week/5 Higher IL-6 levels in high risk group (at all time points)
Interaction time x group (F=2.53, P=0.07) ↑*
↑↓* (high) ↓↑* (low) Elovainio et al (84) Organizational justice ~ 14 years/2 Organizational justice significantly negatively associated with IL-6 in
men (percentage change: -4.5, P=0.01); no associations in women ↓↓ (men)
— (women) Leukocyte count
Lee et al (85) Job stress (objective and subjective job stressors:
low vs. high)
8 months/8 Significant lower level of white blood cells (number of cells per mm3) in high objective job stress group (Mdn=7.17) compared to low (Mdn=8.06, P=0.03)
NS difference between low vs. high subjective job stress
↓↓*
Shirom et al (87) JDCS 18-22 months/1 Workload NS associated with leukocyte count
Control significantly negatively associated in males (β=-0.06, P<0.05), NS associated in females
Social support NS associated with leukocyte count
Demands — Control ↓↓ (men)
Support —
a Higher values in the scales for workplace social support and job control indicated lower social support and lower control, respectively (86).
associations of working conditions and chronic low- grade inflammation merely based on prospective studies.
By building on a higher quality of evidence, this review advances our knowledge on effects of work stressors on chronic low-grade inflammation in employees.
Overall, 23 studies met our inclusion criteria. The extant study base was fragmented with high hetero- geneity in assessed exposures and interventions. We identified four clusters of study types, ie, individual- directed/behavioral (including physical and mental) and organization-directed/structural interventions as well as observational studies.
For workplace physical interventions (k=7), the majority of studies reported reductions in inflammation- related plasma molecules. These interventions primarily aimed at changing individual behavior by adding physical exercises or activity into employees’ work routine (both on- and off-the-job) and were conducted among both sedentary and manual workers. The qualitative finding was corroborated in our meta-analysis demonstrating a medium to strong negative effect of physical exercise interventions (aerobic exercise, walking, yoga, cycling to work) on employees’ CRP levels (d= -0.61; k=5). This resonates well with a previous meta-analysis on studies in non-occupational settings showing that exercise train- ing was associated with a decrease in CRP (91). Our results suggest that exercise interventions are an effective measure to reduce low-grade inflammation in employees.
Concerning mental interventions in the workplace (eg, stress reduction programs, music making), the study base (k=5) was limited and inconclusive. However, there were indications for changes of inflammation-related processes on intra-cellular level, ie, gene expression (65, 72) and transcription factors (69). These interven- tions were also individual-oriented, ie, they aimed at influencing mental processes by providing employees opportunities and skills for increasing their well-being, alleviating stress, facilitating relaxation, strengthen- ing resilience etc. Reviews outside work settings have shown associations of psychosocial interventions, espe- cially cognitive behavior therapy and combined psy- chotherapeutic interventions, with enhanced immune system function (92). In addition, salutogenic effects of mindfulness meditation and yoga practices in combina- tion with mindfulness-based stress reduction regarding specific inflammatory markers have been suggested (93, 94). Yet, these studies included heterogeneous popula- tions, also clinical samples, which can lead to spurious estimates of effects. Our synthesis suggests that in occu- pational settings, individual/behavioral interventions appear to be viable measures to ameliorate dysregulated inflammatory processes, however extended research into workplace mental interventions is warranted.
The study base on organizational/structural inter- ventions was confined, with high RoB (k=4). Despite
indications of responsiveness of CRP and cytokines to organizational changes (73, 80), definite conclusions would be premature. Given the high variety of organi- zational-level workplace interventions and differentiated effects on employee health, further investigations into particular types of organizational interventions, such as work reorganization or work time-related conditions, and their effects on inflammatory markers are necessary (95).
The majority of observational studies (k=7) was based on the JDC(-S) model. Results showed predomi- nately null and/or weak associations. However, there were some indications for beneficial functions of job control and workplace social support as well as for sex-related effects. Conclusions of previous reviews are somewhat conflicting: Whereas Nakata (37) suggested that inflammatory markers might be less sensitive to job strain, Wright et al (38) inferred that workplace stress is positively associated with CRP, especially when measured with the JDC model. Despite the evidence for a close link between personal relationships, including social support amongst others, and immune function (96), we found only three studies on workplace social support and inflammatory outcomes. Consistent with previous reviews we deem future research into resources and potentially beneficial effects of workplace support of particular interest (37).
We also sought to detect studies examining stress reactions in terms of inflammation evoked by work- related ICT use. Ultimately, we identified just one study showing that the application of a web-based health promotion tool modulated TNF-α (66). The extent to which working conditions associated with ICT use or respective workplace interventions affect inflammatory processes needs thus to be further investigated.
Work stress and inflammation: methodological and con- ceptual considerations
For the interpretation of the collected evidence, some pivotal aspects potentially influencing associations of working conditions and inflammation warrant attention.
First, included studies differed tremendously in time lags of follow-ups, spanning a few hours to 14 years, and in numbers, ranging from one to eight follow-up assessments. In longitudinal research the magnitude of effects might vary with the span of the follow-up, ie, whether it corresponds with the true underlying time lag of the outcome under study (43). Multi-wave designs increase the likelihood of detecting effects compared to two-wave designs, and response latencies of respective outcomes may depend on type, intensity, and duration of exposures as well as context factors (43, 97). Thus, differences in follow-up measurements of inflammatory markers may help to explain the disparity in findings of the present studies.
Kaltenegger et al
Moreover, although longitudinal designs are sug- gested to overcome the problems of cross-sectional designs in examining causality, reversed or reciprocal causation and third variables constitute critical issues in longitudinal research (98). As for the question of reverse effects, we are aware of only two of the included observational studies that also tested for associations in the opposite direction in full panel designs, ie, inflam- matory markers on subsequent appraisal of working conditions (86, 87). Concerning influences of third variables, many studies controlled for variables critical in stress physiology, such as sex, age, health behav- iors (eg, physical activity, smoking), body mass index, (hormone) medication, and baseline levels of respective markers. However, studies differed in the selection and number of included covariates, entailing varying degrees of threats to internal validity (see also tables S2 and S3). For the investigation of cause–effect relationships between intervention and outcome, RCT are considered the gold standard; yet this design is often not feasible in occupational settings (99). Notwithstanding, half of the identified interventions were RCT, so we were able to draw our meta-analysis upon a high level of evidence, yet confined study base.
Furthermore, inflammation should not be assessed in isolation with regard to stress but in the light of potential disruptions of interactions and feedback loops with other stress axes. Inflammation is affected by the two major stress systems HPA axis and ANS through complex neuroendocrine-immune cascades and interactions, indicating that the effects of stress system mediators on the inflammatory system are not linear (100). There is consistent evidence that chronic stress is related to alterations in the sensitivity of target tissue to stress sig- nals, most importantly glucocorticoid resistance, which is associated with increases in circulating inflammatory mechanisms (100). Examples of these complex multi- system interdependences are the – at first glance surpris- ing – results of Dunne et al (65), where TNF-α mRNA increased in the IG, and Hasson et al (66), where TNF-α decreased in the CG. Both authors provided post-hoc explanations concerning potentially impaired negative feedback loops with the HPA axis in chronic stress, and Dunne et al proposed that the observed increase could be due to decreases in cortisol following stress reduction in the IG. Anti-inflammatory effects of cortisol have been well-described (100).
Lastly, we focused on working conditions, as they are more modifiable to workplace interventions than personal factors. Nonetheless, we acknowledge that employees’ intrinsic characteristics, such as personal resources, affective-cognitive states, and coping styles, play a significant role in (work) stress perception and regulation (101–103). For instance, higher work engage- ment was found to be associated with lower subsequent
high-sensitivity CRP (104), whereas over-commitment was associated with reduced immunity (39).
Limitations and strengths
Our findings should be interpreted in the light of some limitations. By defining the PECOS/PICOS components, we might have excluded relevant aspects. For example, shiftwork is an important risk factor for inflammation, and in our search, we found sound interventional studies in shift worker samples (eg, 105). However, as it is difficult to disentangle effects of working conditions from the effects of circadian misalignment per se on inflammatory markers (106), we decided a priori to exclude these stud- ies. Moreover, for greater external validity, we only con- sidered investigations in real-world occupational settings.
Notwithstanding, we are aware of high-quality laboratory studies on stress responsiveness in chronic work stress (107, 108) and simulation studies in high-risk profes- sions, such as firefighting (109). The generalizability of our findings is restricted to the working population, yet we included a broad range of different professional and occupational groups. A main limitation of our review is the limited study base with great heterogeneity regard- ing intervention contents and modes of implementation, work exposures, and occupational sectors. By clustering studies following an inductive logic we attempted to build more homogenous subgroups of studies. However, the disparity of clusters in combination with the scarcity of data currently limits the possibility and adequacy of deriving overall conclusions. We acknowledge, that some employer-instigated health promotion approaches were not limited to the workplace and included components to be performed off site/ off duty or on the way to work (eg, cycling to work). This may have introduced heterogene- ity within our clusters and impeded a clear differentiation concerning the nature and implementation of included interventions as well as ensuing inferences concerning effectiveness. An important strength of our investigation is that we developed and determined our methodology prior to the start in a peer-reviewed protocol, limiting the risk of reporting bias and ensuring higher quality.
Further strengths pertain to our pre-defined classification system, which enabled us to draw conclusions per cluster given the high heterogeneity of identified studies, and the consideration of a comprehensive set of inflammatory biomarkers. Furthermore, we applied rigorous and thor- ough RoB assessments in and across studies, allowing for a critical evaluation of the presented evidence.
Implications for occupational health management and future research
For occupational health management, a holistic approach integrating both individual/behavioral and organizational/
